Systems Epigenomics of Persistent Bloodstream Infection

持续性血流感染的系统表观基因组学

• 批准号: 10551703
• 负责人: Michael R Yeaman
• 金额: $ 230.46万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551703
• 关键词: Acceleration; Address; Algorithms; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antifungal Agents; Antigens; Automobile Driving; Bacteremia; Bioinformatics; Blood; Blood Circulation; Candida; Candida albicans; Centers for Disease Control and Prevention (U.S.); Chromosomal Rearrangement; Clinical; Communicable Diseases; Computer Models; Computing Methodologies; DNA Methylation; Data; Data Set; Detection; Diagnostic; Disease; Disseminated candidiasis; Emergency Situation; Epigenetic Process; Etiology; Experimental Models; Fungemia; Gene Expression; Gene Rearrangement; Genetic; Genotype; Goals; Healthcare; Hematogenous; Hospital Mortality; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunologic Memory; Immunotherapeutic agent; In Vitro; Infection; Intensive Care Units; Intervention; Laboratories; Laboratory Study; Length of Stay; Libraries; Life; Macrophage; Mediating; Memory; Methods; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Nosocomial Infections; Organ; Outcome; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Phenotype; Predisposition; Process; Productivity; Receptor Signaling; Refractory; Research; Research Project Grants; Resistance; Risk; STAT protein; STAT1 protein; Sepsis; Specificity; Staphylococcus aureus; Stress; Study models; System; Systems Biology; Technology; Testing; Therapeutic; Tissues; Training; Translating; United States National Institutes of Health; Variant; Virulence; Work; antimicrobial; antimicrobial drug; antimicrobial tolerance; biobank; candidemia; cell injury; chronic infection; complex data; cytokine; data management; effective therapy; epigenetic memory; epigenome; epigenomics; high risk; improved; in vivo; innate immune mechanisms; innovation; insight; methicillin resistant Staphylococcus aureus; methylomics; mortality; mouse model; neutrophil; novel; novel strategies; pathogen; pharmacologic; prediction algorithm; predictive modeling; prevent; programs; prospective; prototype; response; screening; sex; success; synergism; therapeutic candidate; vaccine strategy

PROJECT ABSTRACT Persistent bloodstream infections are life-threatening infectious disease emergencies posing significant challenges to effective treatment. Such infections occur when a pathogen is susceptible to an anti-infective agent in vitro but is not cleared from the bloodstream in vivo when that anti-infective agent is used appropriately. As a result, anti-infective usage increases, accelerating alarming increases in anti-infective resistance. This vicious cycle of persistence driving anti- infective escalation driving resistance is an NIH high–priority concern. Bloodstream infections caused by Staphylococcus aureus (SA) or Candida albicans (CA) are increasingly common. Of urgent concern, up to 35% of patients with methicillin-resistant SA (MRSA) persistent bacteremia succumb even on gold-standard therapy. Likewise, in patients with hematogenously disseminated candidiasis (HDC), mortality is 39% overall and 47% in those in the intensive care unit, despite appropriate treatment. A disease mystery is central to such infections: the causative pathogen is susceptible to antimicrobials in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from classical antibiotic resistance. Rather, persistent MRSA or CA are elusive: they adapt to host immune responses and antibiotic stresses uniquely in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for persistent MRSA or CA bloodstream infections. Hence, there is a critical, unmet need to understand the unique interactions of the human, pathogen and therapeutic factors driving persistence outcomes. Based on our extensive preliminary data, we believe that persistent infections caused by MRSA and CA result from a three-way interaction of the pathogen, host immune response and antimicrobial agent in vivo. We hypothesize that persistent isolates: 1) have specific epigenomes to enable persistence; 2) subvert innate immune programming and memory for immune evasion; 3) evoke non-protective or maladaptive immune responses; and 4) exploit contextual immunity as persistence reservoirs. We further posit that conventional approaches to study this clinically urgent phenomenon are insufficient to understand it. We have developed three independent but synergistic research Projects to overcome these limitations. Each Project brings proven strengths and innovative approaches to bear on Specific Aims that synergize via a systems-based approach supported by outstanding technology, bioinformatics and computational Cores. Here, we will use state-of-the-art technologies to comprehensively analyze the genetics and epigenetics of pathogens and the host immune system in context of antimicrobial therapy in laboratory studies and experimental models of infection. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. By understanding these factors and their interactions, new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. These goals are ideally aligned with priorities of the National Institutes of Health and Centers for Disease Control & Prevention.

项目摘要